Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania that affects many millions of people worldwide. In humans, infection with the parasite manifests either as a cutaneous disease caused mainly by L. major, L. tropica, and L. mexicana; as a mucocutaneous disease caused mainly by L. brasiliensis; or as a visceral disease caused mainly by L. donovani and L. chagasi. In canids, Leishmania infections manifest as a visceral disease that can result in high death rates.
All leishmanial diseases are transmitted to their vertebrate hosts by phlebotomine sand flies, which acquire the pathogen by feeding on infected hosts and transmit them by regurgitating the parasite at the site of a subsequent blood meal (Killick-Kendrick, Biology of Leishmania in phlebotomine sand flies. In Biology of the kinetoplastida. W. Lumsden and D. Evans, editors. Academic Press, New York. 395, 1979).
While obtaining a blood meal, sand flies salivate into the host's skin. This saliva contains anticlotting, antiplatelet, and vasodilatory compounds that increase the hemorrhagic pool where sand flies feed (Ribeiro et al., Comp. Biochem. Physiol. 4:683, 1986; Charlab et al., Proc. Natl. Acad. Sci. USA. 26:15155, 1999). Some of these components are additionally immunomodulatory. For example, the New World sand fly Lutzomyia longipalpis contains the 6.5 kDa peptide, maxadilan, which is the most potent vasodilator known (Lerner et al., J. Biol. Chem. 17:11234, 1991). Maxadilan additionally has immunosuppressive activities of its own (Qureshi et al., Am. J. Trop. Med. Hyg. 6:665, 1996), as do many persistent vasodilators such as prostaglandin E2 (Makoul et al., J. Immunol. 134:2645, 1985; Santoli and Zurier, J. Immunol. 143:1303, 1989; Stockman and Mumford, Exp. Hematol. 2:65, 1974) and calcitonin gene-related peptide (Nong et al., J. Immunol. 1:45, 1989). Old World sand flies do not have maxadilan but instead use adenosine monophosphate and adenosine as vasodilators (Ribeiro et al., J. Exp. Biol. 11:1551, 1999). Adenosine is also an immunomodulatory component, promoting the production of interleukin-10 and suppressing tumor necrosis factor-α and interleukin-12 in mice (Hasko et al., J. Immunol. 10:4634, 1996; Webster, Asian Pac. J. Allergy Immunol. 2:311, 1984; Hasko et al., FASEB J. 14:2065, 2000). Despite what is known about the role of sandfly saliva and disease transmission, much remains unknown, and an effective vaccine does not exist. Thus, there is a need for agents that can be used to induce an immune response to the organisms that cause leishmaniasis.